Not Applicable.
Not Applicable.
This invention relates to compositions and methods for the treatment of degenerative diseases. More specifically, the invention relates to pharmaceutical compositions and methods for the treatment of degenerative diseases related to aggregation or assembly of conformationally altered proteins including, but not limited to Alzheimer""s disease, cerebral amyloid angiopathy, Parkinson""s disease, frontal temporal dementia, Pick""s disease, amyotrophic lateral sclerosis, Huntington""s disease, bovine spongiform encephalopathy and Creutzfeld-Jakob disease.
Assembly or aggregation of conformationally altered proteins is thought to be a major cause of prepathological and pathological conditions including amyloidoses, prion diseases, and other common degenerative diseases. Conformational alterations from xcex1-helical or random coil to xcex2-sheet conformation are believed to be required for the conversion of normally soluble and functional proteins into insoluble and pathogenic states. Examples of such insoluble proteins include: Beta-Amyloid Precursor Protein (APP) and Beta-Amyloid (xcex2A) in amyloid plaques of Alzheimer""s Disease (AD), Familial AD (FAD) and cerebral amyloid angiopathy (CAA); xcex1-synuclein deposits in Lewy bodies of Parkinson""s disease; Tau in neurofibrillary tangles in frontal temporal dementia and Pick""s disease; Superoxide Dismutase in amyotrophic lateral sclerosis; Huntingtin in Huntington""s disease; and Prion Protein (PrP) in Creutzfelds-Jakob disease (CJD). These conformationally altered insoluble proteins are composed mostly of fibrils formed by the assembly or aggregation of xcex2-sheet monomers. It is believed that abnormal binding of a metal ligand in the metal-binding sites of the normal, soluble proteins is a major factor in the pathogenesis and continued pathology of the resulting diseases. It has also been suggested that certain forms of these diseases may be inherited. However, no methods currently exist to definitively link these diseases to genetic inheritance.
Currently, there is no effective therapy for PrP infection. There are also no treatments currently available that target the conformational changes from xcex1-helical or random coil to xcex2-sheet conformation to treat cerebral amyloid angiopathy, Parkinson""s disease, frontal temporal dementia, Pick""s disease, amyotrophic lateral sclerosis, or Huntington""s disease. AD therapeutic agents such as acetylcholinesterase (AChE) inhibitors that enhance cholinergic neurotransmission by hindering the breakdown of acetylcholine have been approved by the FDA. This approach, however, does not retard the progression of the underlying neurodegenerative disease.
Nonspecific chelation therapy has become increasingly promoted as a therapy for AD and other diseases manifested by the aggregation or assembly of conformationally altered proteins. However, the growing practice of intravenous infusions of well-known nonspecific chelators such as ethylene-diamine-tetraacetic acid (EDTA) can lead to systemic metal ion depletion, making its use less desirable.
Therefore, novel compositions and methods are needed to treat diseases caused by the prepathological and pathological assembly or aggregation of proteins causing amyloidoses, prion diseases and other degenerative diseases that inhibit or reverse the progression of the underlying neurodegenerative disease and do not result in metal ion depletion.
In overcoming the above disadvantages, it is an object of the invention to produce compositions that may be used to successfully treat degenerative diseases.
Accordingly, and in one aspect of the invention, a composition capable of solubilizing a conformationally altered protein that includes a carboxylic acid anion of picolinic acid, analogs, or derivatives, thereof and a cation is provided, wherein the composition is not zinc picolinate, chromium picolinate, molybdenum picolinic, iron picolinic, manganese picolinate, copper picolinate, boron picolinate or vanadium picolinate.
In a second aspect of the invention, the above-described composition of the invention comprises picolinic acid, its analogs, or derivatives.
In a third aspect of the invention, the above-described composition of the invention comprises fusaric acid.
In a fourth aspect of the invention, a method of preventing or reversing conformationally altered protein assembly or aggregation in an animal is provided that includes introducing picolinic acid, its analogs, or derivatives to the conformationally altered protein.
In a fifth aspect of the invention, a method of preventing or reversing conformationally altered protein assembly or aggregation in an animal is provided that includes introducing fusaric acid to the conformationally altered protein.
In a sixth aspect of the invention, a method of treating conformationally altered protein assembly or aggregation in an animal is provided that includes administering a therapeutically effective amount of the above-described compositions of the invention.
These and other objects, advantages and features of the invention will become apparent to those persons skilled in the art upon reading the details of the compounds and methods more fully described below.